Joint mouse–human phenome-wide association to test gene function and disease risk

Xusheng Wang,Daniel C Ciobanu,Lu Lu,Alexander O Reznik,Jinsong Huang,William L Taylor,Katherine S Pollard,Johan Auwerx,Robert W Williams,Khyobeni Mozhui,L Darryl Quarles,Zhousheng Xiao,Xinnan Niu,Virginija Jovaisaite,Stanley F Nelson,Junmin Peng,Zugen Chen,John A Capra,Zhengsheng Li,Joshua C Denny,Igor B Zhulin,Lisa Bastarache,Megan K Mulligan,Evan G Williams,Артем Тишков ,Ashutosh Kumar Pandey

doi:10.1038/ncomms10464

Abstract

Phenome-wide association is a novel reverse genetic strategy to analyze genome-to-phenome relations in human clinical cohorts. Here we test this approach using a large murine population segregating for ∼5 million sequence variants, and we compare our results to those extracted from a matched analysis of gene variants in a large human cohort. For the mouse cohort, we amassed a deep and broad open-access phenome consisting of ∼4,500 metabolic, physiological, pharmacological and behavioural traits, and more than 90 independent expression quantitative trait locus (QTL), transcriptome, proteome, metagenome and metabolome data sets—by far the largest coherent phenome for any experimental cohort (www.genenetwork.org). We tested downstream effects of subsets of variants and discovered several novel associations, including a missense mutation in fumarate hydratase that controls variation in the mitochondrial unfolded protein response in both mouse and Caenorhabditis elegans, and missense mutations in Col6a5 that underlies variation in bone mineral density in both mouse and human.

Highlights

Phenome-wide association is a novel reverse genetic strategy to analyze genome-tophenome relations in human clinical cohorts
This family consists of B150 isogenic lines, and as we show here, this family segregates for over five million common variants and B12,000 missense mutations. To accompany these genomic data, we assembled a high-coverage phenome with over 4,500 quantitative metabolic, physiological, pharmacological, toxicological, morphometric and behavioural phenotypes, along with linked references to the primary literature. This BXD phenome includes B90 large open-access expression quantitative trait locus studies generated over the past decade as well as recent metagenomic, metabolomics and proteomic components[8–10]
Some of which were subsequently validated in a large human clinical cohort[6,7]

Summary

Introduction

Phenome-wide association is a novel reverse genetic strategy to analyze genome-tophenome relations in human clinical cohorts. To establish the first murine resource for phenome-wide association, we have used a large cohort of recombinant inbred strains—the BXD family—that were generated by crossing two fully inbred parental strains—C57BL/6J (B6) and DBA/2J (D2) This family consists of B150 isogenic lines, and as we show here, this family segregates for over five million common variants and B12,000 missense mutations. To accompany these genomic data, we assembled a high-coverage phenome with over 4,500 quantitative metabolic, physiological, pharmacological, toxicological, morphometric and behavioural phenotypes, along with linked references to the primary literature This BXD phenome includes B90 large open-access expression quantitative trait locus (eQTL) studies generated over the past decade as well as recent metagenomic, metabolomics and proteomic components[8–10]. This may often be due to a lack of technical sensitivity and power, or due to molecular and developmental compensation

Methods

Results

Conclusion